tbuckley/cabot-search huggingface dataset:
Phase 3 Open-Label Clinical Trial of Elexacaftor/Tezacaftor/Ivacaftor in Children Aged 2–5 Years with Cystic Fibrosis and at Least One <i>F508del</i> Allele
Authors: Jennifer L. Goralski, Jordana E. Hoppe, Marcus A. Mall, Susanna A. McColley, Edward McKone, Bonnie Ramsey, Jonathan H. Rayment, Phil Robinson, Florian Stehling, Jennifer L. Taylor-Cousar, Elizabeth Tullis, Neil Ahluwalia, Anna Chin, Chenghao Chu, Mengdi Lu, Tao Niu, Tanya Weinstock, Felix Ratjen, Margaret Rosenfeld
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Rationale: Elexacaftor/tezacaftor/ivacaftor has been shown to be safe and effective in people with cystic fibrosis (CF) aged ≥6 years with ≥1 F508del-CFTR allele but has not been studied in younger children. Objectives: To evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of elexacaftor/tezacaftor/ivacaftor in children with CF aged 2 through 5 years. Methods: In this Phase 3, open-label, two-part study (Parts A and B), children weighing <14 kg (on Day 1) received elexacaftor 80 mg once daily, tezacaftor 40 mg once daily, and ivacaftor 60 mg each morning and 59.5 mg each evening; children weighing ≥14 kg received elexacaftor 100 mg once daily, tezacaftor 50 mg once daily, and ivacaftor 75 mg every 12 hours. Measurements and Main Results: The primary endpoints for Part A (15-day treatment period) were pharmacokinetics and safety and tolerability. For Part B (24-week treatment period), the primary endpoint was safety and tolerability; secondary endpoints included pharmacokinetics and absolute changes from baseline in sweat chloride concentration and lung clearance index2.5 (LCI2.5) through Week 24. Analysis of pharmacokinetic data from 18 children enrolled in Part A confirmed the appropriateness of the Part B dosing regimen. In Part B, 75 children (F508del/minimal function genotypes, n = 52; F508del/F508del genotype, n = 23) were enrolled and dosed. Seventy-four children (98.7%) had adverse events which were all mild (62.7%) or moderate (36.0%) in severity. The most common adverse events were cough, fever, and rhinorrhea. Decreases in sweat chloride concentration (−57.9 mmol/L [95% confidence interval [CI], −61.3 to −54.6]; n = 69) and LCI2.5 (−0.83 units [95% CI, −1.01 to −0.66]; n = 50) were observed from baseline through Week 24. Mean BMI was within the normal range at baseline and remained stable at Week 24. Conclusions: In this open label study in children 2 through 5 years of age, elexacaftor/tezacaftor/ivacaftor treatment was generally safe and well tolerated, with a safety profile consistent with that observed in older age groups, and led to clinically meaningful reductions in sweat chloride concentration and lung clearance index. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT0453779. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
CD4 <sup>+</sup> T cells produce GM-CSF and drive immune-mediated glomerular disease by licensing monocyte-derived cells to produce MMP12
Authors: Hans-Joachim Paust, Ning Song, Donatella De Feo, Nariaki Asada, Selma Tuzlak, Yu Zhao, Jan-Hendrik Riedel, Malte Hellmig, Amirrtavarshni Sivayoganathan, Anett Peters, Anna Kaffke, Alina Borchers, Ulrich O. Wenzel, Oliver M. Steinmetz, Gisa Tiegs, Elisabeth Meister, Matthias Mack, Christian Kurts, Sibylle von Vietinghoff, Maja T. Lindenmeyer, Elion Hoxha, Rolf A. K. Stahl, Tobias B. Huber, Stefan Bonn, Catherine Meyer-Schwesinger, Thorsten Wiech, Jan-Eric Turner, Burkhard Becher, Christian F. Krebs, Ulf Panzer
Journal: Science Translational Medicine (2023)

GM-CSF in glomerulonephritis Despite glomerulonephritis being an immune-mediated disease, the contributions of individual immune cell types are not clear. To address this gap in knowledge, Paust et al . characterized pathological immune cells in samples from patients with glomerulonephritis and in samples from mice with the disease. The authors found that CD4+ T cells producing granulocyte-macrophage colony-stimulating factor (GM-CSF) licensed monocytes to promote disease by producing matrix metalloproteinase 12 and disrupting the glomerular basement membrane. Targeting GM-CSF to inhibit this axis reduced disease severity in mice, implicating this cytokine as a potential therapeutic target for patients with glomerulonephritis. —CM
A systems approach points to a therapeutic role for retinoids in asparaginase-associated pancreatitis
Authors: Cheng-Yu Tsai, Toshie Saito, Mayur Sarangdhar, Maisam Abu-El-Haija, Li Wen, Bomi Lee, Mang Yu, Den A. Lipata, Murli Manohar, Monique T. Barakat, Kévin Contrepois, Thai Hoa Tran, Yves Theoret, Na Bo, Ying Ding, Kristen Stevenson, Elena J. Ladas, Lewis B. Silverman, Loredana Quadro, Tracy G. Anthony, Anil G. Jegga, Sohail Z. Husain
Journal: Science Translational Medicine (2023)

Among drug-induced adverse events, pancreatitis is life-threatening and results in substantial morbidity. A prototype example is the pancreatitis caused by asparaginase, a crucial drug used to treat acute lymphoblastic leukemia (ALL). Here, we used a systems approach to identify the factors affecting asparaginase-associated pancreatitis (AAP). Connectivity Map analysis of the transcriptomic data showed that asparaginase-induced gene signatures were potentially reversed by retinoids (vitamin A and its analogs). Analysis of a large electronic health record database (TriNetX) and the U.S. Federal Drug Administration Adverse Events Reporting System demonstrated a reduction in AAP risk with concomitant exposure to vitamin A. Furthermore, we performed a global metabolomic screening of plasma samples from 24 individuals with ALL who developed pancreatitis (cases) and 26 individuals with ALL who did not develop pancreatitis (controls), before and after a single exposure to asparaginase. Screening from this discovery cohort revealed that plasma carotenoids were lower in the cases than in controls. This finding was validated in a larger external cohort. A 30-day dietary recall showed that the cases received less dietary vitamin A than the controls did. In mice, asparaginase administration alone was sufficient to reduce circulating and hepatic retinol. Based on these data, we propose that circulating retinoids protect against pancreatic inflammation and that asparaginase reduces circulating retinoids. Moreover, we show that AAP is more likely to develop with reduced dietary vitamin A intake. The systems approach taken for AAP provides an impetus to examine the role of dietary vitamin A supplementation in preventing or treating AAP.
Prior SARS-CoV-2 infection enhances and reshapes spike protein–specific memory induced by vaccination
Authors: Véronique Barateau, Loïc Peyrot, Carla Saade, Bruno Pozzetto, Karen Brengel-Pesce, Mad-Hélénie Elsensohn, Omran Allatif, Nicolas Guibert, Christelle Compagnon, Natacha Mariano, Julie Chaix, Sophia Djebali, Jean-Baptiste Fassier, Bruno Lina, Katia Lefsihane, Maxime Espi, Olivier Thaunat, Jacqueline Marvel, Manuel Rosa-Calatrava, Andres Pizzorno, Delphine Maucort-Boulch, Laetitia Henaff, Mitra Saadatian-Elahi, Philippe Vanhems, Stéphane Paul, Thierry Walzer, Sophie Trouillet-Assant, Thierry Defrance
Journal: Science Translational Medicine (2023)

The diversity of vaccination modalities and infection history are both variables that have an impact on the immune memory of individuals vaccinated against SARS-CoV-2. To gain more accurate knowledge of how these parameters imprint on immune memory, we conducted a long-term follow-up of SARS-CoV-2 spike protein–specific immune memory in unvaccinated and vaccinated COVID-19 convalescent individuals as well as in infection-naïve vaccinated individuals. Here, we report that individuals from the convalescent vaccinated (hybrid immunity) group have the highest concentrations of spike protein–specific antibodies at 6 months after vaccination. As compared with infection-naïve vaccinated individuals, they also display increased frequencies of an atypical mucosa-targeted memory B cell subset. These individuals also exhibited enhanced T H 1 polarization of their SARS-CoV-2 spike protein–specific follicular T helper cell pool. Together, our data suggest that prior SARS-CoV-2 infection increases the titers of SARS-CoV-2 spike protein–specific antibody responses elicited by subsequent vaccination and induces modifications in the composition of the spike protein–specific memory B cell pool that are compatible with enhanced functional protection at mucosal sites.
Neutralization of NET-associated human ARG1 enhances cancer immunotherapy
Authors: Stefania Canè, Roza Maria Barouni, Marina Fabbi, John Cuozzo, Giulio Fracasso, Annalisa Adamo, Stefano Ugel, Rosalinda Trovato, Francesco De Sanctis, Mauro Giacca, Rita Lawlor, Aldo Scarpa, Borislav Rusev, Gabriella Lionetto, Salvatore Paiella, Roberto Salvia, Claudio Bassi, Susanna Mandruzzato, Silvano Ferrini, Vincenzo Bronte
Journal: Science Translational Medicine (2023)

Myeloid cells can restrain antitumor immunity by metabolic pathways, such as the degradation of l-arginine, whose concentrations are regulated by the arginase 1 (ARG1) enzyme. Results from preclinical studies indicate the important role of arginine metabolism in pancreatic ductal adenocarcinoma (PDAC) progression, suggesting a potential for clinical application; however, divergent evolution in ARG1 expression and function in rodents and humans has restricted clinical translation. To overcome this dichotomy, here, we show that neutrophil extracellular traps (NETs), released by spontaneously activated neutrophils isolated from patients with PDAC, create a microdomain where cathepsin S (CTSS) cleaves human (h)ARG1 into different molecular forms endowed with enhanced enzymatic activity at physiological pH. NET-associated hARG1 suppresses T lymphocytes whose proliferation is restored by either adding a hARG1-specific monoclonal antibody (mAb) or preventing CTSS-mediated cleavage, whereas small-molecule inhibitors are not effective. We show that ARG1 blockade, combined with immune checkpoint inhibitors, can restore CD8+ T cell function in ex vivo PDAC tumors. Furthermore, anti-hARG1 mAbs increase the frequency of adoptively transferred tumor-specific CD8+ T cells in tumor and enhance the effectiveness of immune checkpoint therapy in humanized mice. Thus, this study shows that extracellular ARG1, released by activated myeloid cells, localizes in NETs, where it interacts with CTSS that in turn cleaves ARG1, producing major molecular forms endowed with different enzymatic activity at physiological pH. Once exocytosed, ARG1 activity can be targeted by mAbs, which bear potential for clinical application for the treatment of PDAC and require further exploration.
Host-derived mannose glycans trigger a pathogenic γδ T cell/IL-17a axis in autoimmunity
Authors: Inês Alves, Beatriz Santos-Pereira, Noelia de la Cruz, Ana Campar, Vanda Pinto, Pedro M. Rodrigues, Marco Araújo, Sofia Santos, Javier Ramos-Soriano, Carlos Vasconcelos, Roberto Silva, Nuno Afonso, Filipe Mira, Cristina C. Barrias, Nuno L. Alves, Javier Rojo, Lélita Santos, António Marinho, Salomé S. Pinho
Journal: Science Translational Medicine (2023)

Autoimmune diseases are life-threatening disorders that cause increasing disability over time. Systemic lupus erythematosus (SLE) and other autoimmune diseases arise when immune stimuli override mechanisms of self-tolerance. Accumulating evidence has demonstrated that protein glycosylation is substantially altered in autoimmune disease development, but the mechanisms by which glycans trigger these autoreactive immune responses are still largely unclear. In this study, we found that presence of microbial-associated mannose structures at the surface of the kidney triggers the recognition of DC-SIGN-expressing γδ T cells, inducing a pathogenic interleukin-17a (IL-17a)-mediated autoimmune response. Mice lacking Mgat5, which have a higher abundance of mannose structures in the kidney, displayed increased γδ T cell infiltration into the kidney that was associated with spontaneous development of lupus in older mice. N-acetylglucosamine supplementation, which promoted biosynthesis of tolerogenic branched N-glycans in the kidney, was found to inhibit γδ T cell infiltration and control disease development. Together, this work reveals a mannose-γδ T cell-IL-17a axis in SLE immunopathogenesis and highlights glycometabolic reprogramming as a therapeutic strategy for autoimmune disease treatment.
Voices from the picket lines: junior doctors speak out
Authors: Chris Stokel-Walker, Gareth Iacobucci, Elisabeth Mahase, Melina Zachariou, Charlotte Rose
Journal: BMJ (2023)

Junior doctors started a 72 hour walk out on 13 March after the BMA failed to reach any meaningful progress in pay talks with the government.1<b>Chris Stokel-Walker</b>, <b>Gareth Iacobucci</b>, <b>Elisabeth Mahase</b>, <b>Melina Zachariou</b>, and <b>Charlotte Rose</b> spoke to protesters about what drove them to take action
Colonoscopy surveillance: striving toward less is more?
Authors: Monique E. van Leerdam
Journal: Endoscopy (2023)

The National Polyp Study showed that colonoscopy with removal of polyps reduced the incidence of colorectal cancer (CRC) and CRC-related mortality [1]. After a median follow-up time of 16 years, there was a 53 % reduction in CRC-related mortality in the group of patients who underwent removal of adenomas compared with the general population [1]. Although studies have shown the association between findings at index colonoscopy and the risk of metachronous advanced neoplasia [2], there is a lack of evidence about the optimal surveillance interval after polypectomy. Risk estimates used to be mainly based on histology, location, size, and number of adenomas at index colonoscopy. However, there is new evidence showing the risk of metachronous CRC after the removal of serrated polyps [3].
Monocyte migration profiles define disease severity in acute COVID-19 and unique features of long COVID
Authors: Nicholas A. Scott, Laurence Pearmain, Sean B. Knight, Oliver Brand, David J. Morgan, Christopher Jagger, Sarah Harbach, Saba Khan, Halima A. Shuwa, Miriam Franklin, Verena Kästele, Thomas Williams, Ian Prise, Flora A. McClure, Pamela Hackney, Lara Smith, Madhvi Menon, Joanne E. Konkel, Criag Lawless, James Wilson, Alexander G. Mathioudakis, Stefan C. Stanel, Andrew Ustianowski, Gabriella Lindergard, Seema Brij, Nawar Diar Bakerly, Paul Dark, Christopher Brightling, Pilar Rivera-Ortega, Graham M. Lord, Alex Horsley, Karen Piper Hanley, Timothy Felton, Angela Simpson, John R. Grainger, Tracy Hussell, Elizabeth R. Mann
Journal: European Respiratory Journal (2023)

Background COVID-19 is associated with a dysregulated immune response but it is unclear how immune dysfunction contributes to the chronic morbidity persisting in many COVID-19 patients during convalescence (long COVID). Methods We assessed phenotypical and functional changes of monocytes in COVID-19 patients during hospitalisation and up to 9 months of convalescence following COVID-19, respiratory syncytial virus or influenza A. Patients with progressive fibrosing interstitial lung disease were included as a positive control for severe, ongoing lung injury. Results Monocyte alterations in acute COVID-19 patients included aberrant expression of leukocyte migration molecules, continuing into convalescence (n=142) and corresponding with specific symptoms of long COVID. Long COVID patients with unresolved lung injury, indicated by sustained shortness of breath and abnormal chest radiology, were defined by high monocyte expression of C-X-C motif chemokine receptor 6 (CXCR6) (p&lt;0.0001) and adhesion molecule P-selectin glycoprotein ligand 1 (p&lt;0.01), alongside preferential migration of monocytes towards the CXCR6 ligand C-X-C motif chemokine ligand 16 (CXCL16) (p&lt;0.05), which is abundantly expressed in the lung. Monocyte CXCR6 and lung CXCL16 were heightened in patients with progressive fibrosing interstitial lung disease (p&lt;0.001), confirming a role for the CXCR6–CXCL16 axis in ongoing lung injury. Conversely, monocytes from long COVID patients with ongoing fatigue exhibited a sustained reduction of the prostaglandin-generating enzyme cyclooxygenase 2 (p&lt;0.01) and CXCR2 expression (p&lt;0.05). These monocyte changes were not present in respiratory syncytial virus or influenza A convalescence. Conclusions Our data define unique monocyte signatures that define subgroups of long COVID patients, indicating a key role for monocyte migration in COVID-19 pathophysiology. Targeting these pathways may provide novel therapeutic opportunities in COVID-19 patients with persistent morbidity.
Prevalence of human papillomavirus DNA and p16INK4a positivity in vulvar cancer and vulvar intraepithelial neoplasia: a systematic review and meta-analysis
Authors: Zhuang Li, Penglin Liu, Ziying Wang, Zhaoyang Zhang, Zhongshao Chen, Ran Chu, Guiju Li, Qiuyue Han, Yong Zhao, Li Li, Jinwei Miao, Beihua Kong, Kun Song
Journal: The Lancet Oncology (2023)
Effectiveness of nirmatrelvir–ritonavir in preventing hospital admissions and deaths in people with COVID-19: a cohort study in a large US health-care system
Authors: Joseph A Lewnard, John M McLaughlin, Debbie Malden, Vennis Hong, Laura Puzniak, Bradley K Ackerson, Bruno J Lewin, Jeniffer S Kim, Sally F Shaw, Harpreet Takhar, Luis Jodar, Sara Y Tartof
Journal: The Lancet Infectious Diseases (2023)

In the USA, oral nirmatrelvir-ritonavir is authorised for use in patients aged 12 years or older with mild-to-moderate COVID-19 who are at risk of progression to severe disease and hospitalisation. We aimed to establish the effectiveness of nirmatrelvir-ritonavir in preventing hospital admissions and death in people with COVID-19 in an outpatient prescribing context in the USA.
A phosphoglycerate mutase 1 allosteric inhibitor overcomes drug resistance to EGFR-targeted therapy via disrupting IL-6/JAK2/STAT3 signaling pathway in lung adenocarcinoma
Authors: Qian Liang, Miaomiao Gong, Jing-Hua Zou, Ming-yu Luo, Lu-lu Jiang, Cheng Wang, Ning-xiang Shen, Mo-cong Zhang, Lu Xu, Hui-min Lei, Ke-Ren Zhang, Rui Zhang, Guanglei Zhuang, Liang Zhu, Hong-zhuan Chen, Lu Zhou, Ying Shen
Journal: Drug Resistance Updates (2023)

Resistance to epidermal growth factor receptor (EGFR) inhibitors, from the first-generation erlotinib to the third generation osimertinib, is a clinical challenge in the treatment of patients with EGFR-mutant lung adenocarcinoma. Our previous work found that a novel allosteric inhibitor of phosphoglycerate mutase 1 (PGAM1), HKB99, restrains erlotinib resistance in lung adenocarcinoma cells. However, the role of HKB99 in osimertinib resistance and its underlying molecular mechanism remains to be elucidated. Herein, we found that IL-6/JAK2/STAT3 signaling pathway is aberrantly activated in both erlotinib and osimertinib resistant cells. Importantly, HKB99 significantly blocks the interaction of PGAM1 with JAK2 and STAT3 via the allosteric sites of PGAM1, which leads to inactivation of JAK2/STAT3 and thereby disrupts IL-6/JAK2/STAT3 signaling pathway. Consequently, HKB99 remarkably restores EGFR inhibitor sensitivity and exerts synergistic tumoricidal effect. Additionally, HKB99 alone or in combination with osimertinib down-regulated the level of p-STAT3 in xenograft tumor models. Collectively, this study identifies PGAM1 as a key regulator in IL-6/JAK2/STAT3 axis in the development of resistance to EGFR inhibitors, which could serve as a therapeutic target in lung adenocarcinoma with acquired resistance to EGFR inhibitors.
Emerging roles of Aurora-A kinase in cancer therapy resistance
Authors: Dayong Zheng, Jun Li, Han Yan, Gang Zhang, Wei Li, Edward Chu, Ning Wei
Journal: Acta Pharmaceutica Sinica B (2023)

Aurora kinase A (Aurora-A), a serine/threonine kinase, plays a pivotal role in various cellular processes, including mitotic entry, centrosome maturation and spindle formation. Overexpression or gene-amplification/mutation of Aurora-A kinase occurs in different types of cancer, including lung cancer, colorectal cancer, and breast cancer. Alteration of Aurora-A impacts multiple cancer hallmarks, especially, immortalization, energy metabolism, immune escape and cell death resistance which are involved in cancer progression and resistance. This review highlights the most recent advances in the oncogenic roles and related multiple cancer hallmarks of Aurora-A kinase-driving cancer therapy resistance, including chemoresistance (taxanes, cisplatin, cyclophosphamide), targeted therapy resistance (osimertinib, imatinib, sorafenib, etc.), endocrine therapy resistance (tamoxifen, fulvestrant) and radioresistance. Specifically, the mechanisms of Aurora-A kinase promote acquired resistance through modulating DNA damage repair, feedback activation bypass pathways, resistance to apoptosis, necroptosis and autophagy, metastasis, and stemness. Noticeably, our review also summarizes the promising synthetic lethality strategy for Aurora-A inhibitors in RB1, ARID1A and MYC gene mutation tumors, and potential synergistic strategy for mTOR, PAK1, MDM2, MEK inhibitors or PD-L1 antibodies combined with targeting Aurora-A kinase. In addition, we discuss the design and development of the novel class of Aurora-A inhibitors in precision medicine for cancer treatment.
A 3-year course of bulevirtide monotherapy may cure HDV infection in patients with cirrhosis
Authors: Maria Paola Anolli, Elisabetta Degasperi, Lena Allweiss, Angelo Sangiovanni, Marco Maggioni, Caroline Scholtes, Valerie Oberhardt, Christoph Neumann-Haefelin, Maura Dandri, Fabien Zoulim, Pietro Lampertico
Journal: Journal of Hepatology (2023)
Forming new connections: Advances in human stem-cell-derived interneuron therapy for treating epilepsy
Authors: Jyoti Gupta, Janice R. Naegele
Journal: Neuron (2023)

Inhibitory interneuron progenitors capable of integrating into epileptic host circuitry hold great potential for correcting network hyperexcitability and reducing seizures in temporal lobe epilepsy. In this issue of <i>Neuron</i>, Zhu and colleagues<sup>1</sup> report robust seizure suppression by hPSC-derived interneurons up to 9 months post-transplantation, significantly extending the duration observed previously.
Disruption of the ATXN1-CIC complex reveals the role of additional nuclear ATXN1 interactors in spinocerebellar ataxia type 1
Authors: Stephanie L. Coffin, Mark A. Durham, Larissa Nitschke, Eder Xhako, Amanda M. Brown, Jean-Pierre Revelli, Esmeralda Villavicencio Gonzalez, Tao Lin, Hillary P. Handler, Yanwan Dai, Alexander J. Trostle, Ying-Wooi Wan, Zhandong Liu, Roy V. Sillitoe, Harry T. Orr, Huda Y. Zoghbi
Journal: Neuron (2023)

(Neuron 111, 481–492.e1–e8; February 15, 2023) In the originally published paper, there was one error in the STAR Methods section “Generation of Atxn1154Q[V591A;S602D]/2Q and Atxn12Q[V591A;S602D]/2Q mouse models.” When describing the mouse amino acid locations for the two mutations made in the AXH domain of ATXN1, we erroneously stated that human V591 and S602 correspond to mouse V620 and S631, respectively. The corrected text should read “Please note that human V591 and S602 correspond to mouse V566 and S577, respectively.” This has now been updated online. The authors apologize for the error. Disruption of the ATXN1-CIC complex reveals the role of additional nuclear ATXN1 interactors in spinocerebellar ataxia type 1Coffin et al.NeuronDecember 27, 2022In BriefCoffin et al. show that global ablation of the ATXN1-CIC interaction normalizes aberrant SCA1 CIC genome-wide binding in mice; however, it does not correct all transcriptional or behavioral changes. They discovered that ATXN1 interacts with multiple factors to drive SCA1, revealing the mechanistic complexity that underlies regional vulnerability in neurodegenerative diseases. Full-Text PDF Open Access